Refining method of bendamustine hydrochloride

Abstract

The invention provides a refining method of bendamustine hydrochloride, which comprises the following steps: completely dissolving 1 part by weight of bendamustine hydrochloride crude product in 3-10 parts by weight of hydrochloric acid solution with the concentration of 0.01-2mol / L, wherein the temperature is 30-100 DEG C during the dissolution process; and filtering when being hot, cooling, crystallizing, filtering, and drying for obtaining a bendamustine hydrochloride white crystal. The method can effectively remove impurities in the bendamustine hydrochloride crude product, lead the purity of the product to be more than 99.5%, lead single impurity to be not more than 0.1%, and lead the refining yield to be not lower than 90%; in addition, the refining method has simple process, low cost and easy industrial production of the process; and a preparation produced by taking the raw material has few impurities, good efficacy and few adverse reactions, and can bring the greatest benefit to patients with tumors.

Description

Technical field [0001] The invention relates to a method for refining bendamustine hydrochloride, which belongs to the technical field of medicine production. Background technique [0002] The chemical name of bendamustine hydrochloride is [1-methyl-2-(4′-butyric acid)-5-N,N′-bis-(2′-chloroethyl)]-1H-benzimidazole Hydrochloride, the structural formula is: [0003] [0004] Bendamustine hydrochloride was first developed by Ozegowski and his colleagues at the Microbiological Testing Association in Jena, Germany in the early 1860s. The purpose of synthesis is to make an alkylated nitrogen mustard (a non-functional alkylating agent) link a purine and an amino acid. The main advantage of the newly synthesized compound compared with chlorambucil is its water solubility. Anger et al. disclosed the initial clinical results of the successful application of bendamustine to patients with plasmacytoma. Bendamustine was produced by Jena Pharmaceuticals under the trade name Cytostasan from 1...

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Problems solved by technology

Patent WO2009120386 discloses that a refining solvent is ethanol / water (V / V=97 / 3), but in experiments we found that when refining with alcohol solution, a new impurity (esterification product) will be produced because of heating, because benzene Damustine has a carboxyl group and an alcohol undergoes an esterification reaction at high temperature. If the control is not good, the esterification product will inevitably affect the quality of the finished product, and this impurity will be difficult to remove

The final refining method of Chinese patent CN101691359 is to mix and heat the crude product with tetrahydrofuran (70°C), and then slowly add water until the solid dissolves; THF has a low boiling point (66°C), and when heated to reflux according to this patent method, when adding water dropwise, It is prone to bumping, and the method is cumbersome to operate; due to the degradation of bendamustine hydrochloride in the solution, the refining yield is low; tetrahydrofuran is a second-class solvent, which has liver toxicity and accumulation, which will cause different effects on operators and the environment. degree of influence

[0014] Therefore, heat-dissolving and refining bendamustine hydrochloride in water will cause damage to varying degrees, and the purity of the resulting product is relatively poor, especially it is difficult to control a single impurity below 0.1%, which is difficult to meet the requirements of injection raw materials. The quality requirements also fail to meet the relevant technical requirements of the European Union's quality research technical guidelines ICH, the refined yield is also quite low, and the cost is high

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